20 ms·

Antiviral compound blocks SARS-CoV-2 from entering cells

186 points by WaitWaitWha 5y ago

ashtonkem 5y ago
I wonder if they actually used human lung cells for this test; the article doesn’t seem to specify. Past tests have used Vero cells, which are apparently the norm for virology research, but aren’t a good analogue for human cells for Covid infection. This seems to be why some compounds worked well in a Petri dish, but didn’t work in actual humans.
- raphlinus 5y ago
  Here's the actual paper: https://www.pnas.org/content/118/43/e2108728118 https://www.pnas.org/content/118/43/e2108728118 There's a lot of detailed discussion about different types of cells. Vero cells don't have TMPRSS2, but Calu-3 (human lung epithelial) cells do. To dramatically oversimplify, this compound works on the latter type but not the former. They also did a little safety testing in a mouse model. This is early stage, as you point out there are a lot of things that work well in the lab and not so much in real humans, but still I find it promising.
  - ashtonkem 5y ago
    I’m not the best reader of scientific papers, but it looks like they used human lung cells and Vero cells. I’m not qualified to speak to the rest of the experimental design, but it looks like they’ve at least avoided that old mistake. > We analyzed pseudotype entry driven by the spike protein of SARS-CoV-2 (SARS-2-S) or the glycoprotein of vesicular stomatitis virus (VSV-G) into the TMPRSS2-positive human lung cell line Calu-3 (7, 29). VSV-G was used as a control, as it does not depend on TMPRSS2 for host cell entry. Besides Calu-3 cells, we further used Vero cells (African green monkey, kidney) as a control, as these cells do not express TMPRSS2, and therefore any reduction in SARS-2-Sdriven entry would be related to either unspecific side effects or cytotoxicity.
dukeofdoom 5y ago
I was reading that the flue shot also works against covid according to a study. The world will learn to live with covid. I'm more worried about the authoritarians taking advantage of the current crisis.
- loonster 5y ago
  I remember reading in 2020 that those that have received a TB vaccine had better results with Covid. I never did find out if there was a co confounding variable that explains it. (I wouldn't be surprised if it does.)
whatanorigtht 5y ago
We already have a treatment that works fine. Get some ivermectin and chill.
- throwoutway 5y ago
  > We already have a treatment that works fine. Get some ivermectin and chill. This isn’t a helpful comment. Please read the hacker news guidelines
  - whatanorigtht 5y ago
    It is helpful. Ivermectin works so well Pfizer is copying it.
    - robflynn 5y ago
      https://apnews.com/article/fact-checking-067310377629 https://apnews.com/article/fact-checking-067310377629
      - whatanorigtht 5y ago
        Sorry, I don't care to read your government propaganda.
      - ccn0p 5y ago
        I find fact checkers quite interesting in the way they've been deployed over the last few years. As if one source is the "truth" and that settles things. Usually when you get to the end of "false" claims, you find some tidbits that make you wonder... such as: "Several posts circulating online wrongly suggest that the pills are the same because ivermectin also acts like a protease inhibitor and keeps the virus from replicating. Ivermectin continues to be studied in relation to COVID-19, however, it has yet to be proven that it can treat COVID-19."
        deleted 5y ago
        [deleted]
raphlinus 5y ago
I'm starting to get pretty optimistic. There seem to be a bunch of antivirals with very different mechanisms of action - this one blocks entry of the virus to cells, Molnupiravir fucks up accurate replication of the virus (nucleoside analog), others are protease inhibitors, which are very effective against HIV. There's a caveat, most treatments that look promising don't pan out, but there are a lot in the pipeline and it seems likely that some will. What I think will happen is a cocktail of antivirals, and together these will significantly reduce the mortality. We need that, because it looks like the virus will probably be circulating endemically. The other great thing about a cocktail (as opposed to a single antiviral) is that the virus developing resistance is both less likely and less of a problem if it does happen.
- angelzen 5y ago
  > Molnupiravir [interferes with] accurate replication of the virus At first glance this sound like a really bad idea, given that the #1 concern is future covid mutations.
  - ralusek 5y ago
    It specifically causes non-viable mutations. Therefore, the concern isn't currently that it'll cause mutations in the virus and create new strains, but rather that we have to be very confident that it isn't resulting in mutagenicity in mammalian cells. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136050/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136050/
    - angelzen 5y ago
      Thanks, I wasn't aware of that.
- ashtonkem 5y ago
  mRNA vaccines look extremely promising too. It’s entirely possible that some classes of cancer will be effectively eliminated in our lifetime because of it, along with HIV and/or Malaria. The latter would probably be the biggest reduction in human death and misery since the invention of the Polio vaccine
twofornone 5y ago
Interesting. So this drug, in addition to the novel compound being developed as a covid treatment by Pfizer, is a protease inhibitor, targeting TMPRSS specifically...just like a certain "horse dewormer" from recent memory[0]. Yeah, I know, "in vitro". Did you also know that the emergency vaccine authorization is explicitly contingent on there being "no adequate, approved, and available alternative to the product" for covid19[1]? Very interesting indeed. 0. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203399/#!po=12.9213 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203399/#!po=12... 1. https://www.google.com/amp/s/theconversation.com/amp/what-are-emergency-use-authorizations-and-do-they-guarantee-that-a-vaccine-or-drug-is-safe-151178 https://www.google.com/amp/s/theconversation.com/amp/what-ar... NOTE: it's getting hard to search for sources that mention this fact, and now that what little faith I've had in our institutions has effectively been destroyed, I suspect this is an emergent, collective, deliberate exclusion. Wouldn't want to give the proles any strange ideas about "conspiracy theories" and such.
penagwin 5y ago
> PNAS October 26, 2021 118 (43) e2108728118; https://doi.org/10.1073/pnas.2108728118 https://doi.org/10.1073/pnas.2108728118 I'm curious how was this published October 26, 2021? (Currently Oct 15)
- vidanay 5y ago
  Probably the date of the print publication.
- beakerbreaker 5y ago
  That's the real advance! :) PNAS recently moved to a continuous publication process so the paper comes out in the planned issue whenever ready rather than effectively coming out twice: once ahead-of-print and once in the issue. https://www.pnas.org/page/updates#pnas-continuous-publication https://www.pnas.org/page/updates#pnas-continuous-publicatio...
nekt 5y ago
This blocks TMPRSS2 which is the exact protein ivermectin blocks.
- space_fountain 5y ago
  Some quick googling doesn’t back this up and my understanding is that ivermectin has only shown itself to be effective at doses that are higher then are remotely safe. It also just isn’t the sort of thing there would be incentive to lie about. Probably then the straightforward story is true no it’s only effective as prescribed as treatment for parasites. If you’d like to provide some sources though or more explanation that would be great. Note that TMPRSS2 has been a potential target for treating covid basically since the beginning, so some one lying and claiming it as a mechanism of action isn’t surprising
  - nekt 5y ago
    Well you're wrong. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996102/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996102/ "Ivermectin was found as a blocker of viral replicase, protease and human TMPRSS2."
    - analyte123 5y ago
      Computer docking simulations don't prove anything and are only possibly useful for initial drug screening.
      - nekt 5y ago
        He said ivermectin was not found to block TMPRSS2. I linked a nih study that said it did. Now its about proving its efficacy against sars-cov-2? I believe this is called "moving the goalposts". And there we have it - in silico is fine for this new substance that will likely have a huge price tag. Not fine for an existing generic. Far fewer people are buying this nonsense these days.
        5y ago
elevenoh 5y ago
Inconvenient to vaccine mandates & pharma lobbyists, so will we see it prescribed?
- tinus_hn 5y ago
  It is patented so who knows! Now instead of having to compete on producing cheap generic medicine, pharma can ask the proper question: how much are you willing to pay to be saved!
vfclists 5y ago
I can't believe it's not Ivermectin

186 points by WaitWaitWha 5y ago

I wonder if they actually used human lung cells for this test; the article doesn’t seem to specify. Past tests have used Vero cells, which are apparently the norm for virology research, but aren’t a good analogue for human cells for Covid infection. This seems to be why some compounds worked well in a Petri dish, but didn’t work in actual humans.

raphlinus 5y ago
Here's the actual paper: https://www.pnas.org/content/118/43/e2108728118 https://www.pnas.org/content/118/43/e2108728118 There's a lot of detailed discussion about different types of cells. Vero cells don't have TMPRSS2, but Calu-3 (human lung epithelial) cells do. To dramatically oversimplify, this compound works on the latter type but not the former. They also did a little safety testing in a mouse model. This is early stage, as you point out there are a lot of things that work well in the lab and not so much in real humans, but still I find it promising.
- ashtonkem 5y ago
  I’m not the best reader of scientific papers, but it looks like they used human lung cells and Vero cells. I’m not qualified to speak to the rest of the experimental design, but it looks like they’ve at least avoided that old mistake. > We analyzed pseudotype entry driven by the spike protein of SARS-CoV-2 (SARS-2-S) or the glycoprotein of vesicular stomatitis virus (VSV-G) into the TMPRSS2-positive human lung cell line Calu-3 (7, 29). VSV-G was used as a control, as it does not depend on TMPRSS2 for host cell entry. Besides Calu-3 cells, we further used Vero cells (African green monkey, kidney) as a control, as these cells do not express TMPRSS2, and therefore any reduction in SARS-2-Sdriven entry would be related to either unspecific side effects or cytotoxicity.

dukeofdoom 5y ago

I was reading that the flue shot also works against covid according to a study. The world will learn to live with covid. I'm more worried about the authoritarians taking advantage of the current crisis.

loonster 5y ago
I remember reading in 2020 that those that have received a TB vaccine had better results with Covid. I never did find out if there was a co confounding variable that explains it. (I wouldn't be surprised if it does.)

whatanorigtht 5y ago

We already have a treatment that works fine. Get some ivermectin and chill.

throwoutway 5y ago
> We already have a treatment that works fine. Get some ivermectin and chill. This isn’t a helpful comment. Please read the hacker news guidelines
- whatanorigtht 5y ago
  It is helpful. Ivermectin works so well Pfizer is copying it.
  - robflynn 5y ago
    https://apnews.com/article/fact-checking-067310377629 https://apnews.com/article/fact-checking-067310377629
    - whatanorigtht 5y ago
      Sorry, I don't care to read your government propaganda.
    - ccn0p 5y ago
      I find fact checkers quite interesting in the way they've been deployed over the last few years. As if one source is the "truth" and that settles things. Usually when you get to the end of "false" claims, you find some tidbits that make you wonder... such as: "Several posts circulating online wrongly suggest that the pills are the same because ivermectin also acts like a protease inhibitor and keeps the virus from replicating. Ivermectin continues to be studied in relation to COVID-19, however, it has yet to be proven that it can treat COVID-19."
      - deleted 5y ago
        [deleted]

raphlinus 5y ago

I'm starting to get pretty optimistic. There seem to be a bunch of antivirals with very different mechanisms of action - this one blocks entry of the virus to cells, Molnupiravir fucks up accurate replication of the virus (nucleoside analog), others are protease inhibitors, which are very effective against HIV. There's a caveat, most treatments that look promising don't pan out, but there are a lot in the pipeline and it seems likely that some will. What I think will happen is a cocktail of antivirals, and together these will significantly reduce the mortality. We need that, because it looks like the virus will probably be circulating endemically. The other great thing about a cocktail (as opposed to a single antiviral) is that the virus developing resistance is both less likely and less of a problem if it does happen.

angelzen 5y ago
> Molnupiravir [interferes with] accurate replication of the virus At first glance this sound like a really bad idea, given that the #1 concern is future covid mutations.
- ralusek 5y ago
  It specifically causes non-viable mutations. Therefore, the concern isn't currently that it'll cause mutations in the virus and create new strains, but rather that we have to be very confident that it isn't resulting in mutagenicity in mammalian cells. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136050/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136050/
  - angelzen 5y ago
    Thanks, I wasn't aware of that.
ashtonkem 5y ago
mRNA vaccines look extremely promising too. It’s entirely possible that some classes of cancer will be effectively eliminated in our lifetime because of it, along with HIV and/or Malaria. The latter would probably be the biggest reduction in human death and misery since the invention of the Polio vaccine

twofornone 5y ago

Interesting. So this drug, in addition to the novel compound being developed as a covid treatment by Pfizer, is a protease inhibitor, targeting TMPRSS specifically...just like a certain "horse dewormer" from recent memory[0]. Yeah, I know, "in vitro". Did you also know that the emergency vaccine authorization is explicitly contingent on there being "no adequate, approved, and available alternative to the product" for covid19[1]? Very interesting indeed. 0. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203399/#!po=12.9213 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203399/#!po=12... 1. https://www.google.com/amp/s/theconversation.com/amp/what-are-emergency-use-authorizations-and-do-they-guarantee-that-a-vaccine-or-drug-is-safe-151178 https://www.google.com/amp/s/theconversation.com/amp/what-ar... NOTE: it's getting hard to search for sources that mention this fact, and now that what little faith I've had in our institutions has effectively been destroyed, I suspect this is an emergent, collective, deliberate exclusion. Wouldn't want to give the proles any strange ideas about "conspiracy theories" and such.

penagwin 5y ago

> PNAS October 26, 2021 118 (43) e2108728118; https://doi.org/10.1073/pnas.2108728118 https://doi.org/10.1073/pnas.2108728118 I'm curious how was this published October 26, 2021? (Currently Oct 15)

vidanay 5y ago
Probably the date of the print publication.
beakerbreaker 5y ago
That's the real advance! :) PNAS recently moved to a continuous publication process so the paper comes out in the planned issue whenever ready rather than effectively coming out twice: once ahead-of-print and once in the issue. https://www.pnas.org/page/updates#pnas-continuous-publication https://www.pnas.org/page/updates#pnas-continuous-publicatio...

nekt 5y ago

This blocks TMPRSS2 which is the exact protein ivermectin blocks.

space_fountain 5y ago
Some quick googling doesn’t back this up and my understanding is that ivermectin has only shown itself to be effective at doses that are higher then are remotely safe. It also just isn’t the sort of thing there would be incentive to lie about. Probably then the straightforward story is true no it’s only effective as prescribed as treatment for parasites. If you’d like to provide some sources though or more explanation that would be great. Note that TMPRSS2 has been a potential target for treating covid basically since the beginning, so some one lying and claiming it as a mechanism of action isn’t surprising
- nekt 5y ago
  Well you're wrong. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996102/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996102/ "Ivermectin was found as a blocker of viral replicase, protease and human TMPRSS2."
  - analyte123 5y ago
    Computer docking simulations don't prove anything and are only possibly useful for initial drug screening.
    - nekt 5y ago
      He said ivermectin was not found to block TMPRSS2. I linked a nih study that said it did. Now its about proving its efficacy against sars-cov-2? I believe this is called "moving the goalposts". And there we have it - in silico is fine for this new substance that will likely have a huge price tag. Not fine for an existing generic. Far fewer people are buying this nonsense these days.
      - 5y ago

elevenoh 5y ago

Inconvenient to vaccine mandates & pharma lobbyists, so will we see it prescribed?

tinus_hn 5y ago
It is patented so who knows! Now instead of having to compete on producing cheap generic medicine, pharma can ask the proper question: how much are you willing to pay to be saved!

vfclists 5y ago

I can't believe it's not Ivermectin